The Xin repeat-containing protein, mXinβ, initiates the maturation of the intercalated discs during postnatal heart development.
The Xin repeat-containing protein, mXinβ, initiates the maturation of the intercalated discs during postnatal heart development.
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DOI：
10.1016/j.ydbio.2012.12.007
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发表时间：
2013-02-15
影响因子：
2.7
通讯作者：
Lin, Jim Jung-Ching
中科院分区：
文献类型：
--
作者：
Wang, Qinchuan;Lin, Jenny Li-Chun;Chan, Stephen Y.;Lin, Jim Jung-Ching
关键词：
闰盘（intercalateddisc，ICD）是心脏的一种独特结构，在心肌细胞间的通讯和信号传导中起着重要作用。ICD在出生后发育期间通过细胞间连接的深刻再分布以及心肌细胞末端200多种蛋白质的募集和组装而形成和成熟。这一过程的分子机制尚未完全了解。人心肌病相关（CMYA）/Xin肌动蛋白结合重复序列蛋白（XIRP）基因（分别为CMYA 1/XIRP 1和CMYA 3/XIRP 2）的小鼠直系同源物（mXinα和mXinβ）编码定位于ICD的蛋白质。消融mXinα导致成人迟发性心肌病伴传导缺陷和mXinβ上调。ICD结构缺陷见于成人mXinα-null心脏，而非幼年mXinα-null心脏。另一方面，mXinβ的缺失导致出生后16.5天的ICD缺陷，这是心脏形成ICD的发育阶段，表明mXinβ是ICD形成所必需的。本研究采用定量Western blot方法，发现在心肌细胞从侧膜到终末的细胞间连接重新分布过程中，mXinβ而非mXinα表达上调。在缺乏mXinβ的情况下，细胞间连接未能被限制在细胞的末端，并且这种缺陷的发生与mXinβ的峰值表达相关。免疫荧光染色和亚细胞分级显示mXinβ优先与ICD形成相关，进一步表明mXinβ在局部发挥促进ICD成熟的作用。相比之下，mXinα的时空表达谱以及mXinα−/−;mXinβ−/−双敲除心脏中没有比mXinβ−/−心脏更严重的ICD缺陷，表明mXinα对于出生后ICD的形成不是必需的。提出了ICD发展的两步模型，其中mXinβ对于细胞间连接组分从侧点到细胞末端的重新分布至关重要。
The intercalated disc (ICD) is a unique structure to the heart and plays vital roles in communication and signaling among cardiomyocytes. ICDs are formed and matured during postnatal development through a profound redistribution of the intercellular junctions, as well as recruitment and assembly of more than 200 proteins at the termini of cardiomyocytes. The molecular mechanism underlying this process is not completely understood. The mouse orthologs (mXinα and mXinβ) of human cardiomyopathy-associated (CMYA)/Xin actin-binding repeat-containing protein (XIRP) genes (CMYA1/XIRP1 and CMYA3/XIRP2, respectively) encode proteins localized to ICDs. Ablation of mXinα results in adult late-onset cardiomyopathy with conduction defects and up-regulation of mXinβ. ICD structural defects are found in adult but not juvenile mXinα-null hearts. On the other hand, loss of mXinβ leads to ICD defects at postnatal day 16.5, a developmental stage when the heart is forming ICDs, suggesting mXinβ is required for ICD formation. Using quantitative Western blot, we showed in this study that mXinβ but not mXinα was uniquely up-regulated during the redistribution of intercellular junction from the lateral membrane of cardiomyocytes to their termini. In the absence of mXinβ, the intercellular junctions failed to be restricted to the termini of the cells, and the onset of such defect correlated with the peak expression of mXinβ. Immunofluorescence staining and subcellular fractionation showed that mXinβ preferentially associated with the forming ICDs, further suggesting that mXinβ functioned locally to promote ICD maturation. In contrast, the spatiotemporal expression profile of mXinα and the lack of more severe ICD defects in mXinα−/−;mXinβ−/− double knockout hearts than in mXinβ−/− hearts suggested that mXinα was not essential for the postnatal formation of ICDs. A two-step model for the development of ICD is proposed where mXinβ is essential for the redistribution of intercellular junction components from the lateral puncta to the cell termini.
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